JP3211892B2 - Nitric oxide donor and method for treating anal disease - Google Patents
Nitric oxide donor and method for treating anal diseaseInfo
- Publication number
- JP3211892B2 JP3211892B2 JP50083596A JP50083596A JP3211892B2 JP 3211892 B2 JP3211892 B2 JP 3211892B2 JP 50083596 A JP50083596 A JP 50083596A JP 50083596 A JP50083596 A JP 50083596A JP 3211892 B2 JP3211892 B2 JP 3211892B2
- Authority
- JP
- Japan
- Prior art keywords
- anal
- nitroglycerin
- pharmaceutical composition
- pain
- disease
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Abstract
Description
【発明の詳細な説明】 技術分野 この発明は、肛門裂傷、肛門潰瘍、痔疾および挙筋痙
縮のような肛門疾患を冒された部分またはその近傍に局
所塗布することによって治療する組成物及び方法に関す
る。Description: FIELD OF THE INVENTION The present invention relates to compositions and methods of treating anal disorders such as anal fissures, anal ulcers, hemorrhoids and levator spasm by topical application at or near the affected area. .
背景技術 一般に、肛門裂傷、潰瘍、急性痔疾および挙筋痙縮
は、全ての年令、人種および性に影響を与える肛門管の
良性状態である。しかしながら、これらの状態は治療す
るには問題があり、我慢できない痛みの場合は不便であ
る。肛門裂傷または潰瘍は末端肛門管の粘膜または内層
組織の裂傷または潰瘍である。肛門裂傷／潰瘍は他の全
身性または局部的疾患と関係するが、しばしば孤立した
ものとして存在する。転移的な特発性の裂傷または潰瘍
は肛門粘膜に限定され、一般に後部正中線の鋸歯状線の
末端に存在する。肛門裂傷または潰瘍をもった人はしば
しば肛門痛と出血を経験する。そしてその痛みは通じの
時およびその後に著しい。BACKGROUND ART In general, anal fissures, ulcers, acute hemorrhoids and levator spasm are benign conditions of the anal canal that affect all ages, races and sexes. However, these conditions are problematic to treat and inconvenient in the case of unbearable pain. An anal laceration or ulcer is a laceration or ulcer of the mucosa or lining tissue of the distal anal canal. Anal fissures / ulcers are associated with other systemic or local diseases but are often present as isolated. Metastatic idiopathic lacerations or ulcers are confined to the anal mucosa and are generally located at the end of the posterior midline serrated line. Individuals with anal fissures or ulcers often experience anal pain and bleeding. And the pain is remarkable at the time of communication and thereafter.
痔疾は肛門粘膜の下の特定の血管領域である。徴候的
な痔疾患は出血、血栓および／または痔組織の脱出症を
特徴とする。一般に、痔内部組織が排便中に肛門管に張
り出て、出血と痛みをもたらす。その組織が大きくなる
に伴い、出血と痛みが強くなり、脱出症と血栓が続く。
痔の血栓は出血と痛みの別の原因である。Hemorrhoids are specific vascular areas beneath the anal mucosa. Symptomatic hemorrhoidal disease is characterized by bleeding, thrombus and / or prolapse of hemorrhoidal tissue. In general, hemorrhoidal internal tissue protrudes into the anal canal during defecation, causing bleeding and pain. As the tissue grows, bleeding and pain increase, followed by prolapse and thrombus.
Hemorrhoid clots are another cause of bleeding and pain.
挙筋痙縮は、男性より女性に多く影響を与える状態で
ある。この症候群は肛門挙筋、肛門括約筋錯体の一部の
痙性を特徴とする。挙筋痙縮を受ける患者は激しい偶発
的な直腸痛を感じる。身体検査は恥骨直腸筋の痙縮を示
し、その痛みはこの筋を直接圧迫すると再生する。この
状態に出血は伴わない。Levator spasm is a condition that affects women more than men. This syndrome is characterized by spasticity of the levator ani muscle, part of the anal sphincter complex. Patients with levator spasm experience severe accidental rectal pain. Physical examination shows spasticity of the puborectal muscle, the pain of which regenerates when the muscle is pressed directly. No bleeding is associated with this condition.
これら肛門疾患の根本的原因は殆んどわかっていない
が、これらの状態の全てが括約筋高張性の相対度または
絶対度に関係する。肛門裂傷／潰瘍の場合、その異常性
は肛門内部括約筋の未不詳問題にあると思われる。その
内部括約筋は直腸の内円形筋肉層から生じる特殊な不随
意筋である。典型的な肛門裂傷／潰瘍疾患の苦しむ人か
ら得た肛門内圧測定は種々の刺激に対応して拡大された
圧力を示す。その異常に高い肛門内圧は内部括約筋によ
って生じ、裂傷または潰瘍の非治癒およびそれに伴う痛
みの原因となる。Although the underlying cause of these anal diseases is largely unknown, all of these conditions are related to the relative or absolute degree of sphincter hypertonia. In the case of anal fissures / ulcers, the abnormality may be due to an unknown problem of the internal anal sphincter. The internal sphincter is a special involuntary muscle originating from the inner circular muscle layer of the rectum. Intra-anal pressure measurements obtained from a person suffering from a typical anal fissure / ulcer disease show an increased pressure in response to various stimuli. The abnormally high intra-anal pressure is caused by the internal sphincter, causing non-healing of the laceration or ulcer and the associated pain.
肛門管における異常圧レスポンスは痔疾患に苦しむ人
にも見られる。高い肛門内圧はこの状態の発生の主要因
である。急性の痔疾に伴う痛みは一部肛門内部括約筋の
痙縮に起因するといわれている。同様に、挙筋痙縮に伴
う痛みは筋痙縮身体による。Abnormal pressure response in the anal canal is also found in people suffering from hemorrhoidal disease. High intraanal pressure is a major factor in the occurrence of this condition. The pain associated with acute hemorrhoids is said to be due in part to spasticity of the internal anal sphincter. Similarly, the pain associated with levator spasm is due to the muscle spasm body.
これらの肛門疾患の治療に種々の治療法が工案されて
いる。典型的な非手術治療はバルク緩下薬および坐浴を
含む。坐浴は肛門括約筋の弛緩を誘導するので有用であ
る。これに関しては、Shafik,“Role of warm−water
bath in anorectal Conditions:Thethermosphinct
eric reflex",J.Clin.Gastroenterol.,16:304−308,19
93を参照されたい。Various treatments have been devised for the treatment of these anal diseases. Typical non-surgical treatments include bulk laxatives and sham baths. Sit baths are useful because they induce relaxation of the anal sphincter. See Shafik, “Role of warm-water
bath in anorectal Conditions: Thethermosphinct
eric reflex ", J. Clin. Gastroenterol., 16: 304-308,19.
See 93.
肛門局部治療も治癒の促進、痛みの軽減、および腫脹
並びに炎症の低減に用いられている。局部麻酔薬、コル
チコステロイド、収れん薬、等を含む多くの製剤が研究
されてきた。しかしながら、これらの製剤はいずれも治
癒の時間を短縮したり、痛みを軽減したことを示してい
ない。Anal local treatment has also been used to promote healing, reduce pain, and reduce swelling and inflammation. Many formulations have been studied, including local anesthetics, corticosteroids, astringents, and the like. However, none of these preparations has shown any reduction in healing time or pain.
場合によって、手術によって肛門疾患を治療すること
ができる。薬剤治療ができない肛門裂傷／潰瘍または痔
疾の場合はしばしば外科治療と呼ぶ。肛門裂傷／潰瘍の
提案された病因と一致して、それに対する最近の標準外
科処置は側方内部肛門括約筋切開である。この処置にお
いて、肛門内部括約筋は部分的に切断され、それによっ
て肛門内圧を下げる。低下した圧力によって裂傷／潰瘍
を治癒させると共に痛みを除去する。痔の外科手術は余
分の痔組織を除去し、多くの外科医は肛門管圧を下げる
ために付随する制限された肛門内部括約筋切除を行なう
が、挙筋痙縮の外科治療は成功していない。In some cases, surgery can be used to treat anal disease. Anal lacerations / ulcers or hemorrhoids that cannot be treated with drugs are often referred to as surgical treatment. Consistent with the proposed etiology of anal fissure / ulcer, the current standard surgical procedure for it is a lateral internal anal sphincterotome. In this procedure, the internal anal sphincter is partially severed, thereby reducing the anal pressure. Reduced pressure heals lacerations / ulcers and eliminates pain. Hemorrhoid surgery removes excess hemorrhoidal tissue and many surgeons perform concomitant limited internal anal sphincterectomy to reduce anal canal pressure, but surgical treatment for levator spasm has not been successful.
最近、腸神経系（ENS）として知られる自立神経の第
３成分が記載説明されている。それは腸神経からなり、
従来の自律系の外因性輸出入神経のプロセスからなる。
この系は腸の運動と分泌作用を調節する。ENSの注目さ
れる特徴は、腸神経が含有し放出する種々の化学メッセ
ンジャーであることである。アセチルクロリンおよびノ
ルエピネフイリンの外に、種々のペプチドおよび非ペプ
チド物質が確認されており、それらはENSにおける神経
伝達物質と考えられる。そこでは、非アドレナリン、非
コリン作用（NANC）抑制作用が重要であると考えられ
る。Recently, a third component of the autonomic nerve known as the enteric nervous system (ENS) has been described. It consists of the enteric nerve,
It consists of the extrinsic import and export neural processes of the traditional autonomous system.
This system regulates intestinal motility and secretory effects. A notable feature of ENS is that it is a variety of chemical messengers that the enteric nerve contains and releases. In addition to acetylchlorin and norepinephrine, various peptide and non-peptide substances have been identified, which are considered neurotransmitters in ENS. There, non-adrenergic, non-cholinergic (NANC) inhibitory effects may be important.
さらに最近、窒素酸化物（NO）が筋肉への抑制伝達物
質として確認された。NOは動物および人間における肛門
直腸の抑制反射を仲介することが示された。例えば、次
の刊行物を参照されたい： Rattan et al.,“Nitric Oxide pathway in re
ctoanal inhibitory reflex of Opossum internal
anal sphincter,"Gastroenterology,103:43−50,199
2;Chakder et al.,“Release of nitric oxide b
y activation of nonadrenergic noncholinergic
neurons of internal anal sphincter,“Am.J.Phys
iol.,264:G7−G12,1993;O′Kelley et al.,“Nerve
mediated relaxation of the internal anal sph
incter:The role of nitric oxide,"Gut,34:689−6
83,1993;Gillespie et al.,“Influence of haemog
lobin and erythrocytes on the effects of ED
RF,a smooth muscle inhibitory factor,and nitr
ic oxide on vasculer and non−vascular smoot
h muscle,"Br.J.Pharmacol.,95:1151−1156,1988;Igna
rro et al.,“Nitric oxideand cyclic GMP form
ation upon electrical field stimulation cause
relaxation of corpus cavernosum smooth musc
le,"Biochem.Biophys.Res.Commun.,170:843−850,1990;
Bult et al.,“Nitric oxide as an inhibitroy
non−adrenergic non−cholinergic neurotransmit
ter,"Nature,345:346−3471990. システインの存在下で触媒される種々の有機ニトレー
トからの非酵素的NO放出に基づくNOの生成が可溶性グア
ニル酸シクラーゼの直接または間接活性化をもたらし、
最終的に生体における脈管平滑筋の弛緩をもたらすと提
案されている。More recently, nitrogen oxides (NO) have been identified as inhibitory transmitters to muscle. NO has been shown to mediate the anorectal inhibitory reflex in animals and humans. See, for example, the following publication: Rattan et al., “Nitric Oxide pathway in re
ctoanal inhibitory reflex of Opossum internal
anal sphincter, "Gastroenterology, 103: 43-50,199
2; Chakder et al., “Release of nitric oxide b
y activation of nonadrenergic noncholinergic
neurons of internal anal sphincter, “Am.J.Phys
iol., 264: G7-G12, 1993; O'Kelley et al., "Nerve
mediated relaxation of the internal anal sph
incter: The role of nitric oxide, "Gut, 34: 689-6
83, 1993; Gillespie et al., “Influence of haemog
lobin and erythrocytes on the effects of ED
RF, a smooth muscle inhibitory factor, and nitr
ic oxide on vasculer and non-vascular smoot
h muscle, "Br.J.Pharmacol., 95: 1511-1156,1988; Igna
rro et al., “Nitric oxideand cyclic GMP form
ation upon electrical field stimulation cause
relaxation of corpus cavernosum smooth musc
le, "Biochem. Biophys. Res.Commun., 170: 843-850, 1990;
Bult et al., “Nitric oxide as an inhibitroy
non-adrenergic non-cholinergic neurotransmit
ter, "Nature, 345: 346-3471990. Production of NO based on non-enzymatic NO release from various organic nitrates catalyzed in the presence of cysteine results in direct or indirect activation of soluble guanylate cyclase;
It has been proposed to ultimately result in relaxation of vascular smooth muscle in vivo.
例えば、次の刊行物を参照： Feelisch et al.,“Correlation between nitric
oxide formation during degradation of organ
ic nitrates and activation of guanylate cycl
ase,"Eur.J.Pharmacol.,139:19−30,1987;およびFung
et al.,“Biochemical mechanism of organic nit
rate action,"Am.J.Cardiol.,70:4B−10B.1992. ニトログリセリン（GTN）、イソソルビドジニトレー
ト（ISDN）、イソソルビドモノニトレート（ISMN）、エ
リトリチルテトラニトレート（ETN）、ペンタエリトリ
チルテトラニトレート（PETN）のような有機ニトレート
は血管拡張をすることが知られ、数十年の間狭心症の治
療に使用されてきた。例えば、次の刊行物を参照： Huff et al.（Eds.），“Physicians′Desk Refer
ence,"41st Edition,Madical Economics Company,Or
adell,N.J.,1987,at pages 780,1176−78,1533 and
1984−85;Rubin,U.S.patent 5,059,603（Oct.199
1）;Budavari et al.（Eds.），“The Merck Inde
x,"llth Edition,Merck ＆ Co.,Rahway,N.J.,1989,
p.821（isopropyl nitrate）;Fung et al.,“Bioche
mical mechanism of organic nitrate action,"A
m.J.Cardiol.,79:4B−10B,1992. ヒドロコルチゾンのようなコルチコステロイドが種々
の良性肛門疾患の治療に長年使用されてきた。この治療
の研究は若干の利点を示したが、再現性も有効な方法が
示されていない。For example, see the following publication: Feelisch et al., “Correlation between nitric
oxide formation during degradation of organ
ic nitrates and activation of guanylate cycl
ase, "Eur. J. Pharmacol., 139: 19-30, 1987; and Fung.
et al., “Biochemical mechanism of organic nit
rate action, "Am. J. Cardiol., 70: 4B-10B.1992. Nitroglycerin (GTN), isosorbide dinitrate (ISDN), isosorbide mononitrate (ISMN), erythrityl tetranitrate (ETN), pentaerythritol Organic nitrates, such as trityltetranitrate (PETN), are known to vasodilate and have been used for the treatment of angina for decades, see, for example, the following publication: Huff et al. . (Eds.), “Physicians'Desk Refer
ence, "41st Edition, Madical Economics Company, Or
adell, NJ, 1987, at pages 780,1176−78,1533 and
1984-85; Rubin, USpatent 5,059,603 (Oct. 199
1); Budavari et al. (Eds.), “The Merck Inde.
x, "llth Edition, Merck & Co., Rahway, NJ, 1989,
p.821 (isopropyl nitrate); Fung et al., “Bioche
mical mechanism of organic nitrate action, "A
mJ Cardiol., 79: 4B-10B, 1992. Corticosteroids such as hydrocortisone have been used for the treatment of various benign anal disorders for many years. Studies of this treatment have shown some benefits, but reproducibility has not shown an effective method.
シブカイン、リドカイン、プラモキシン、等のような
局所麻酔薬が肛門痛の治療に使用されてきたが、いずれ
も短時間の軽減であった。例えば、次の刊行物を参照： Suzuki et al.,U.S.patent 4,292,299（Sep.198
1）,note column ５ lines 18−20 ＆26−28;Rubi
n 603.note column 7,lines 61−65 ＆ example
1;Greiner,U.S.patent 5,183,663（Feb.1993）;Will
iams,U.S patent 4,118,480（Oct.1978）;Huff et
al.（Eds.），“The Merck Index,"llth Edition,pa
ge 198. 発明の開示 本発明の目的は、肛門裂傷、肛門潰瘍、痔疾および挙
筋痙縮のような肛門疾患の有効治療並びに該疾患に伴う
痛みの迅速軽減をすることである。Local anesthetics such as sibucaine, lidocaine, pramoxine, and the like have been used to treat anal pain, all with a short relief. See, for example, the following publication: Suzuki et al., USpatent 4,292,299 (Sep. 198).
1), note column 5 lines 18-20 &26-28; Rubi
n 603.note column 7, lines 61-65 & example
1; Greiner, USpatent 5,183,663 (Feb. 1993); Will
iams, US patent 4,118,480 (Oct. 1978); Huff et
al. (Eds.), “The Merck Index,” llth Edition, pa
ge 198. Disclosure of the Invention It is an object of the present invention to provide an effective treatment for anal diseases such as anal fissures, anal ulcers, hemorrhoids and levator spasm, and a rapid relief of the pain associated with such diseases.
本発明の別の目的は、かかる肛門疾患の治療に使用で
きる有機窒素酸化物供与体を含有する組成物の提供にあ
る。Another object of the present invention is to provide a composition containing an organic nitrogen oxide donor that can be used for treating such anal diseases.
また、本発明の目的は、冒された部分に有機ニトレー
トからの放出によって送出される有効量の窒素酸化物を
接触させることによって、かかる肛門疾患を治療する方
法を提供することにある。It is also an object of the present invention to provide a method of treating such anal disorders by contacting the affected area with an effective amount of nitrogen oxides delivered by release from organic nitrates.
本発明の別の目的は、かかる肛門疾患の治療に使用で
きるコルチコステロイドおよび／または局所麻酔薬と共
に有機窒素酸化物供与体を含有する組成物の提供にる。Another object of the present invention is to provide a composition comprising an organic nitric oxide donor together with a corticosteroid and / or a local anesthetic which can be used in the treatment of such anal diseases.
さらに、本発明の目的は、冒された部分に有機ニトレ
ートからの放出によって送出される有効量の窒素酸化物
とコルチコステロイドおよび／または局所麻酔薬を接触
させることによって、かかる肛門疾患を治療する方法を
提供することにある。It is a further object of the present invention to treat such anal disorders by contacting the affected area with an effective amount of nitric oxide delivered by release from organic nitrate and a corticosteroid and / or a local anesthetic. It is to provide a method.
本発明のこれらおよび他の目的を達成するために、本
発明は、担体、任意にコルチコステロイドおよび／また
は局所麻酔薬と共に有機窒素酸化物供与体から成り、肛
門疾患の治療に有効な製薬組成物を提供する。一実施態
様において、有機窒素酸化物供与体がニトログリセリン
のみであって組成物が軟質パラフィンまたは石油をベー
スにした軟膏の場合には、ニトログリセリンは0.5重量
％を除く量、そして任意に0.2、１および／または２重
量％を除く量で存在する。ここでの重量％は全て組成物
の全重量を基準にしている。別の面における本発明は、
適当な肛門部分に有効量の窒素酸化物、望ましくは有機
窒素酸化物供与体からの放出により送出される窒素酸化
物を接触させることからなる肛門疾患を治療する方法に
関する。該方法は、コルチコステロイドおよび／または
局所麻酔薬を肛門部分に任意に塗布することも含む。本
発明は、肛門疾患、特に肛門裂傷、肛門潰瘍、痔疾およ
び挙筋痙縮の治療に有効である。多くの患者において、
副作用を弱めることなく治療をすることができる。本発
明の組成物によって肛門痛が迅速かつ効果的に押えるこ
とができる。To achieve these and other objects of the present invention, the present invention provides a pharmaceutical composition comprising an organic nitric oxide donor together with a carrier, optionally a corticosteroid and / or a local anesthetic, which is effective in the treatment of anal disease. Offer things. In one embodiment, when the organic nitrogen oxide donor is only nitroglycerin and the composition is a soft paraffin or petroleum based ointment, the nitroglycerin is present in an amount other than 0.5% by weight, and optionally 0.2, It is present in an amount excluding 1 and / or 2% by weight. All weight percentages herein are based on the total weight of the composition. In another aspect, the invention provides
A method for treating anal disease comprising contacting a suitable anal portion with an effective amount of nitrogen oxides, preferably nitrogen oxides delivered by release from an organic nitrogen oxide donor. The method also includes optionally applying a corticosteroid and / or a local anesthetic to the anal portion. The present invention is effective in treating anal diseases, particularly anal fissures, anal ulcers, hemorrhoids and levator spasm. In many patients,
Treatment can be done without compromising side effects. The anal pain can be quickly and effectively suppressed by the composition of the present invention.
発明を実施するための最良の形態 本願明細書における用語「肛門」は、肛門および／ま
たは下部腸近傍または肛門の筋系および血管系組織を含
む。用語「肛門疾患」は、肛門および／または下部腸近
傍または肛門の筋系および／または血管系を含む組織の
障害または疾患を意味する。用語「有機窒素酸化物供与
体」は、生理的または肛門疾患治療条件下で窒素酸化物
を放出できる有機化合物または該化合物の少なくとも１
つの混合物を意味する。BEST MODE FOR CARRYING OUT THE INVENTION As used herein, the term “anus” includes muscular and vascular tissues near the anus and / or lower intestine or in the anus. The term "anal disease" refers to a disorder or disease of tissues including the anus and / or the lower intestine or the muscular and / or vascular system of the anus. The term “organic nitrogen oxide donor” refers to an organic compound or at least one of the compounds capable of releasing nitrogen oxides under physiological or anal disease treatment conditions.
Means one mixture.
本発明は、例えば、肛門裂傷、肛門潰瘍、痔および／
または挙筋痙縮を含む肛門疾患の根本原因の治療に関す
る。一般に、これら疾患の原因は肛門括約筋の不詳異常
であると考えられる。The present invention provides, for example, anal fissures, anal ulcers, hemorrhoids and / or
Or for the treatment of the underlying causes of anal disease, including levator spasm. In general, the cause of these diseases is thought to be an unknown abnormality of the anal sphincter.
本発明による治療に有効な組成物は、坐剤の形態を含
む適当な局所的形態にすることができる。生理的に許容
される適当な担体を利用して、任意にコルチコステロイ
ドおよび／または局所麻酔薬のような他の薬剤と共に有
機窒素酸化物供与体を含有させる。本発明による肛門疾
患の治療法は適当な源からの窒素酸化物を利用する。A therapeutically effective composition according to the present invention can be in any suitable topical form, including suppository forms. Utilizing a suitable physiologically acceptable carrier, an organic nitrogen oxide donor is optionally included with other agents, such as a corticosteroid and / or a local anesthetic. The method of treating anal disease according to the present invention utilizes nitrogen oxides from a suitable source.
本発明は患者の治療薬に使用される。本発明の有機窒
素酸化物供与体は、硝酸エステルを含み、次の一般式に
よって表されるような非環式または環式化合物を含む少
なくとも１つの有機窒化物を含む： Ｒ（−CR′Ｒ″−Ｏ−NO2）Ｘ 但し、式中のＲは、有機またはＨ（ヒドロ）成分または
共有結合、望ましくは 炭素原子数が２〜12の炭化水素または酸素置換炭化水
素、特に２〜６の炭素と０〜２の酸素を有するもの； Ｒ′は、有機またはＨ成分または共有結合、望ましく
はメチル；エチル、プロピル、ブチル、ペンチルおよび
ヘキシルを含む低級アルキル；メオキシ；低級アルコキ
シ；またはヒドロ（Ｈ）である； Ｒ″は、有機またはヒドロ成分または共有結合、望ま
しくはメチル、低級アルキル、メトキシ、低級アルコキ
シ、またはヒドロ、特にヒドロ；および ｘは、１〜12の整数で、２〜６が望ましい。The invention finds use in the treatment of patients. The organic nitrogen oxide donor of the present invention comprises a nitrate ester and comprises at least one organic nitride comprising an acyclic or cyclic compound as represented by the general formula: R (-CR'R "-O-NO 2) X in the formula, R organic or H (hydro) component or a covalent bond, preferably 2 to 12 carbon atoms hydrocarbon or oxygen-substituted hydrocarbon, especially 2-6 R 'is an organic or H moiety or a covalent bond, preferably methyl; lower alkyl, including ethyl, propyl, butyl, pentyl and hexyl; meoxy; lower alkoxy; or hydro (H R '' is an organic or hydro moiety or a covalent bond, desirably methyl, lower alkyl, methoxy, lower alkoxy, or hydro, especially hydro; and x is 1-12 An integer from 2 to 6 is preferable.
例えば、有機硝酸エステルはエチレングリコールジニ
トレート；イソプロピルニトレート；グリセリル−１−
モノニトレート；グリセリル−1,2−ジニトレート；グ
リセリル−1,3−ジニトレート；ニトログリセリン（GT
N）；ブタン−1,2,4−トリオール−トリニトレート；エ
リトリチルテトラニトレート（ETN）；ペンタエリトリ
チルテトラニトレート（PETN）；イソソルビドモノニト
レート（ISMN）（これはイソソルビド−２−モノニトレ
ート（ISZN）および／またはイソソルビド−５−モノニ
トレート（IS5N）を含む；および／またはイソソルビド
ジニトレート（ISDN）、等にすることができる。望まし
い有機硝酸エステルはGTN、ISDN、ETN、PETN、等であっ
て、それらは他のヒト用薬剤の分野における治療用に規
制認可されている。For example, organic nitrates are ethylene glycol dinitrate; isopropyl nitrate; glyceryl-1-
Mononitrate; glyceryl-1,2-dinitrate; glyceryl-1,3-dinitrate; nitroglycerin (GT
N); butane-1,2,4-triol-trinitrate; erythrityl tetranitrate (ETN); pentaerythrityl tetranitrate (PETN); isosorbide mononitrate (ISMN) (this is isosorbide-2-mononitrate ( ISZN) and / or isosorbide-5-mononitrate (IS5N); and / or isosorbide dinitrate (ISDN), etc. Preferred organic nitrates are GTN, ISDN, ETN, PETN, etc. , They are regulatoryly approved for treatment in the field of other human medicines.
一般に、有機硝酸エステルを含む有機窒素酸化物供与
体は肛門疾患の治療に有効な量で存在する。本発明の典
型的な実施における有機窒素酸化物供与体は約0.01〜10
重量％の濃度で存在する。本明細書における重量％は全
て組成物の全重量を基準にしている。GTNが有機硝酸エ
ステルの場合、望ましい濃度は約0.01〜５重量％の範囲
である。次の表は、本発明の組成物における他の有機硝
酸エステルの特定の一般的範囲のいくつかを示す。Generally, the organic nitric oxide donor, including the organic nitrate, is present in an amount effective for treating anal disease. The organic nitrogen oxide donor in a typical practice of the present invention may comprise from about 0.01 to 10
It is present at a concentration of% by weight. All weight percentages herein are based on the total weight of the composition. When the GTN is an organic nitrate, the desired concentration ranges from about 0.01 to 5% by weight. The following table shows some of the specific general ranges of other organic nitrates in the compositions of the present invention.
化合物 重 量 ％ ISDN 0.01〜7.5（望ましくは、0.3〜３） ETN 0.01〜４（望ましくは、0.1〜1.5） PETN 0.01〜４（望ましくは、0.1〜1.5） 任意に、コルチコステロイドを本発明の組成物に存在
させることができる。例えば、そのコルチコステロイド
はヒドロコルチゾン、すなわち、11−17−21−トリヒド
ロキシ−４−プレグネン−3,20−ジオン、ヒドロコルチ
ゾン21−ナトリウムサクシネート、ヒドロコルチゾンテ
ブテート、コスチコステロン、コルチコステロンアセテ
ート、コルチゾン、コルチゾンアセテート、コルチゾン
21B−シクロペンタンプロピオネート、コルチゾンホス
フェート、トリアミノロンヘキサアセトリド、デキサメ
タゾンホスフェート、デソニド、ベータメタゾンジプロ
ピオネート、モメタゾンフラート、等を含む。 Compound weight% ISDN 0.01 to 7.5 (preferably 0.3 to 3) ETN 0.01 to 4 (preferably 0.1 to 1.5) PETN 0.01 to 4 (preferably 0.1 to 1.5) Optionally, a corticosteroid of the present invention may be used. It can be present in the composition. For example, the corticosteroid is hydrocortisone, i.e., 11-17-21-trihydroxy-4-pregnene-3,20-dione, hydrocortisone 21-sodium succinate, hydrocortisone tebutate, costicosterone, corticosterone acetate. , Cortisone, cortisone acetate, cortisone
Includes 21B-cyclopentanepropionate, cortisone phosphate, triaminolone hexaacetide, dexamethasone phosphate, desonide, beta methasone dipropionate, mometasone flate, and the like.
一般に、コレステロイドは肛門疾患の治療に有効な量
存在させる。本発明の典型的な実施において、コルチコ
ステロイドは約0.001〜10重量％、望ましくは約0.1〜５
重量％の濃度で存在させる。コルスチゾルがそのコルチ
コステロイドの場合の望ましい濃度は約0.5〜2.5重量％
の範囲にある。ヒドロコルチゾンの場合の濃度は約0.5
〜５重量％の範囲にある。デキサメタゾンの場合の濃度
は約0.005〜0.03重量％の範囲にある。Generally, the cholesteroid is present in an amount effective for treating anal disease. In a typical practice of the invention, the corticosteroid is present in an amount of about 0.001-10% by weight, preferably about 0.1-5%.
It is present at a concentration of% by weight. If corstisol is the corticosteroid, the preferred concentration is about 0.5-2.5% by weight
In the range. The concentration for hydrocortisone is about 0.5
-5% by weight. Concentrations for dexamethasone range from about 0.005 to 0.03% by weight.
任意に、本発明の組成物に局所麻酔薬を存在させるこ
とができる。例えば、その局部麻酔剤はジブカイン、リ
ドカイン、プラモキシン、ベンゾカイン、テトラカイ
ン、等を含む。一般に、局部麻酔薬は肛門疾患の治療に
有効な量存在させる。本発明の実施における局部麻酔薬
は、組成物の全重量を基準にして約0.1〜５重量％、望
ましくは約0.5〜４重量％の濃度で存在させる。局部麻
酔薬がジブカインの場合の好適濃度は約0.25〜２重量％
の範囲にある。ベンゾカインの場合の望ましい濃度は約
10〜20重量％の範囲にある。テトラカインの場合の好適
な濃度は約１〜２重量％の範囲にある。Optionally, a local anesthetic can be present in the compositions of the present invention. For example, the local anesthetic includes dibucaine, lidocaine, pramoxine, benzocaine, tetracaine, and the like. Generally, the local anesthetic will be present in an amount effective for treating anal disease. The local anesthetic in the practice of the present invention is present at a concentration of about 0.1-5% by weight, preferably about 0.5-4% by weight, based on the total weight of the composition. When the local anesthetic is dibucaine, the preferred concentration is about 0.25 to 2% by weight.
In the range. The preferred concentration for benzocaine is about
It is in the range of 10-20% by weight. Suitable concentrations for tetracaine are in the range of about 1-2% by weight.
コルチコステロイドと局部麻酔薬は本発明の実施に一
緒に使用される。当業者は、局部投与に適当な調剤状
態、例えば液体、エーロゾル、増粘液体、エマルショ
ン、半固体、粉末、錠剤またはカプセル（それは肛門に
挿入するためになめらかにする）、等の状態で配合す
る。本発明の方法は、特定の場合の治療に適当なように
かかる全ての配合を用いることができる。組成物は便利
な投与形態、例えば増粘溶液やローションを含む増粘
剤、クリームおよびゲルを含む軟こう、等に配合するこ
とができる。Corticosteroids and local anesthetics are used together in the practice of the present invention. Those skilled in the art will formulate in a formulation suitable for topical administration, such as a liquid, aerosol, thickening liquid, emulsion, semi-solid, powder, tablet or capsule, which will be smooth for insertion into the anus. . The method of the present invention can use all such formulations as appropriate for the particular case of treatment. The compositions can be formulated in convenient dosage forms, for example, thickening agents, including thickening solutions and lotions, ointments, including creams and gels.
増粘溶液またはローションおよび軟膏を、活性成分と
種々のゲル化剤や他の増粘剤を混和することによって生
成される、そしてそれらは塗布時または塗布後に活性成
分を皮膚や組織に放出させる。これらの形態は、さらに
低粘度の組成物の場合に生じる恐れのある皮膚や組織か
らの流出を少なくするするために使用するのに有利であ
る。また、それらは活性成分および浸透促進剤の処理表
面との長期接触をさせ、従って活性成分の皮下への送出
速度を高めて正確かつ制御自在の投与をする。かかるタ
イプの組成物によって溢流および組成物との望ましくな
い接触も最少限にすることができる。Thickening solutions or lotions and ointments are produced by mixing the active ingredient with various gelling agents and other thickening agents, which release the active ingredient to the skin or tissues during or after application. These forms are also advantageous for use to reduce outflow from the skin and tissues that can occur with low viscosity compositions. Also, they provide prolonged contact of the active ingredient and the penetration enhancer with the treated surface, thus increasing the rate of subcutaneous delivery of the active ingredient for accurate and controllable administration. Overflow and undesired contact with the composition can also be minimized by such types of compositions.
水分散性増粘剤、すなわち、ポリエチレングリコール
および類似体のような水に分散して均一な分散液または
溶液を生成する剤（それらは組成物に配合される水また
は他の希釈剤と容易に相容性である）を使用することが
有利である。あるいは、エマルシヨン基材を用いてその
リポイド相の柔軟化作用と共に必要な増粘作用を与える
ことができる。Water-dispersible thickeners, ie, agents that disperse in water to form a uniform dispersion or solution, such as polyethylene glycol and analogs, which are readily compatible with water or other diluents incorporated into the composition Which are compatible). Alternatively, the emulsion base material can be used to impart the necessary thickening action together with the softening action of the lipoid phase.
水溶性または水分散性増粘用基材または物質は、組成
物に混和させる活性剤の必要な稠度および濃度に依存し
て種々の粘度のポリエチレングリコール、等を使用す
る。使用に適する他の増粘剤は、限度ではないが水分散
性ガム、カルボキシビニルポリマー、メチルセルロー
ス、ナトリウムカルボキシメチルセルロースおよびアル
ギン酸塩を含む。Water-soluble or water-dispersible thickening substrates or substances use polyethylene glycols of various viscosities, depending on the required consistency and concentration of the active agent to be incorporated into the composition. Other thickeners suitable for use include, but are not limited to, water-dispersible gums, carboxyvinyl polymers, methylcellulose, sodium carboxymethylcellulose and alginates.
エマルシヨン基材を混合するローションおよび軟こう
は、普通の成分を含んで、アセチルアルコールのような
脂肪アルコール、硫酸ラウリル、水のような乳化剤を含
む基材を提供する。また、局部配合剤の残部は、一種以
上の通常の軟こう成分、例えばホワイトペトロラタム、
ラノリン、蒸留水、および鉱物油を通常の量含有する。
坐薬の残部は、酸化亜鉛および／またはココアバターの
ような既知坐薬成分を通常の量含有する。Lotions and ointments which mix the emulsion base with the usual ingredients provide a base with a fatty alcohol such as acetyl alcohol, lauryl sulfate, and an emulsifier such as water. Also, the balance of the topical combination is one or more common ointments, such as white petrolatum,
Contains normal amounts of lanolin, distilled water, and mineral oil.
The remainder of the suppository will contain conventional amounts of known suppository ingredients such as zinc oxide and / or cocoa butter.
注入できる調剤投与量を用意して目盛容器または一定
の容積、例えば５、10cc、等の容器に分配する。さらに
大きい容器、例えば、20cc以上の容器は便利な多重回投
与形態を与えることができる。典型的に１回の投与量、
例えば約0.5〜10gの活性成分を含有する容器は便利な投
与形態を与えることができる。ローションおよび軟膏の
絞り出しチューブおよび綿棒塗布体を用いて、水状の粘
度からさらに粘性の増粘組成物に及ぶ液体および粉末の
組成物の局部塗布をすることができる。An injectable dosage is prepared and dispensed into a scale container or a container of fixed volume, for example, 5, 10 cc. Larger containers, eg, 20 cc or larger, can provide convenient multiple dose forms. Typically a single dose,
For example, a container containing about 0.5-10 g of active ingredient may provide a convenient dosage form. The squeeze tube and swab applicator of lotions and ointments can be used to locally apply liquid and powder compositions ranging from watery viscosities to more viscous thickening compositions.
微粉も使用できる。例えば、デンプンやタルクのよう
な不活性成分を用いて活性成分を粉末状に希釈すること
ができる。Fine powder can also be used. For example, the active ingredient can be diluted into a powder with an inert ingredient such as starch or talc.
本発明の組成物および方法における成分シエーカー、
ダスチング装置、ミスチング装置およびエーロゾルボト
ルからのようなダスチング、噴霧またはミスチングによ
って投与できる。組成物の容器は適当な量および濃度の
成分を装てんする。前記のように、容器は水性希釈剤、
任意の増粘剤、生理的食塩水、等と共に活性剤の混合体
少なくとも約10重量％を含有する流体製剤を装てんす
る。液体組成物は、例えばゲル化剤および／または界面
活性剤の量に依存して低粘度物質の半固体ゲルまたはム
ースとして投与される。かかる組成物は噴霧によって分
与するのに十分な流体または容器からのミストにするこ
とができると共に、浸透性の基準を満たすことができ
る。Component shaker in the compositions and methods of the present invention;
Administration can be by dusting, spraying or misting, such as from dusting devices, misting devices and aerosol bottles. A container of the composition is loaded with the appropriate amount and concentration of the ingredients. As mentioned above, the container is an aqueous diluent,
A fluid formulation containing at least about 10% by weight of the mixture of active agents with optional thickeners, saline, etc., is loaded. Liquid compositions are administered, for example, as semisolid gels or mousses of low viscosity materials, depending on the amount of gelling agent and / or surfactant. Such compositions can be of sufficient fluid or mist from the container to be dispensed by spraying and can meet the criteria of permeability.
本発明による治療において、本発明の活性成分または
組成物の所定量が、望ましくは有機窒素酸化物供与体か
らの放出により送出される有効量の窒素酸化物が投与さ
れるように、冒された肛門部分またはその近傍に接触ま
たは塗布される。使用される活性成分または組成物の量
は、肛門疾患の回復、管理および／または治癒、および
その疾患に伴う痛みの迅速かつ劇的軽減に有効でなけれ
ばならない。例えば、本発明の軟膏組成物は外部肛門お
よび末端の肛門管に指や塗布体で局部的に塗布すること
ができる。あるいは、その薬剤を坐薬として直腸内に送
出させることができる。該薬剤は、このように、例えば
軟膏の場合に日に３回以上、または坐薬の場合に日に１
回以上投与することができる。In treatment according to the present invention, a predetermined amount of an active ingredient or composition of the present invention is affected, such that an effective amount of nitric oxide delivered, preferably by release from an organic nitric oxide donor, is administered. Contact or application at or near the anus. The amount of active ingredient or composition employed should be effective in the amelioration, management and / or cure of the anal disease, and the rapid and dramatic relief of the pain associated with the disease. For example, the ointment composition of the present invention can be applied topically to the external anus and the distal anal canal with a finger or applicator. Alternatively, the drug can be delivered into the rectum as a suppository. The drug may thus be administered, for example, three or more times a day in the case of ointments or one day in the case of suppositories.
It can be administered more than once.
本発明の実施に任意のコルチコステロイドおよび／ま
たは局部麻酔薬の使用は決定的に有利な結果を与える。
活性治療剤として有機硝酸エステルを活性治療剤として
単独での治療が痛みの軽減および／または治癒に失敗す
る場合には、有機硝酸エステルと共にコルチコステロイ
ドおよび／または局部麻酔剤の使用によって痛みの完全
軽減がない場合に効果があり、その上完全治癒がない場
合に効果があることが特に注目される。The use of any corticosteroid and / or local anesthetic in the practice of the present invention will provide decisive beneficial results.
If treatment with organic nitrate alone as the active therapeutic agent alone fails to relieve and / or heal pain, the use of corticosteroids and / or local anesthetics together with the organic nitrate will result in complete pain relief. It is particularly noteworthy that it works when there is no relief, and when there is no complete healing.
本発明による痛みの軽減は迅速かつ劇的である。 The pain relief according to the invention is quick and dramatic.
実 施 例 次の実施例は本発明をさらに説明する。実施例におけ
る全ての部およびパーセント（％）は特にことわらない
限り重量表示である。EXAMPLES The following examples further illustrate the present invention. All parts and percentages (%) in the examples are by weight unless otherwise specified.
実施例 １ ホワイト・ペトロラタム、ラノリンおよび蒸留水中の
濃度が２％のニトログリセリン（E.Fougera ＆ Co.製
のニトログリセリン軟膏、USP ２％）15.5gと、ホワイ
ト・ペトロラタム37.5g（USP.ワセリン,Chesebrough−P
onds USA Co.製）を研究室の混合容器内で室温におい
て混合することによって軟膏を調製した。得られた混合
物は0.5％ニトログリセリン軟膏50gであった。Example 1 15.5 g of white petrolatum, lanolin and 2% nitroglycerin in distilled water (nitroglycerin ointment from E. Fougera & Co., USP 2%) and 37.5 g of white petrolatum (USP. Chesebrough-P
onds USA Co.) in a laboratory mixing vessel at room temperature to prepare an ointment. The resulting mixture was 50 g of 0.5% nitroglycerin ointment.
実施例 ２ ホワイト・ペテロラタム、ラノリンおよび蒸留水中の
濃度が２％のニトログリセリン（実施例１に同じ）12.5
gの軟膏を、ホワイト・ペトロラタムおよび軽鉱物油中
の濃度が2.5％のヒドロコルチゾン（Clay−Park Labs.
社製のヒドロコルチゾン軟膏、USP ２％）20gおよびホ
ワイト・ペテロラタム（USP,ワセリン、実施例１に同
じ）17.5gとを研究室の混合容器内で室温において混合
した。得られた混合物は0.5％ニトログリセリン−１％
ヒドロコルチゾン軟膏50gであった。Example 2 Nitroglycerin at a concentration of 2% in white petrolatum, lanolin and distilled water (same as in Example 1) 12.5
g of ointment is treated with 2.5% hydrocortisone in white petrolatum and light mineral oil (Clay-Park Labs.
20 g of Hydrocortisone Ointment, USP 2%) and 17.5 g of white petrolatum (USP, Vaseline, same as in Example 1) were mixed at room temperature in a laboratory mixing vessel. The resulting mixture is 0.5% nitroglycerin-1%
The amount of hydrocortisone ointment was 50 g.
実施例 ３ ２％ニトログリセリン（実施例１に同じ）12.5gの軟
膏を、ホワイト・ペトロラタム、軽鉱物油、アセトン重
亜硫酸ナトリウム、ラノリン、および蒸留水中の濃度が
１％のジブカイン（USP,Ciba Consnmer Pharmaceutic
als社の商品名NUPERCAINAL）25gおよびホワイト・ペト
ロラタム（実施例１に同じ）12.5gとを研究室用混合容
器内で室温において混合した。得られた混合物は0.5％
ニトログリセリン−0.5％ジブカイン軟膏50gであった。Example 3 12.5 g ointment of 2% nitroglycerin (as in Example 1) was added to white petrolatum, light mineral oil, sodium acetone bisulfite, lanolin, and dibucaine (USP, Ciba Consnmer) at a concentration of 1% in distilled water. Pharmaceutic
als (trade name: NUPERCAINAL) and 25 g of white petrolatum (as in Example 1) were mixed at room temperature in a laboratory mixing vessel. 0.5% of the resulting mixture
Nitroglycerin-0.5% dibucaine ointment 50 g.
実施例 ４ 実施例１と同一の２％ニトログリセリン2.5gの軟膏を
実施例２と同一の2.5％ヒドロコルチゾン20g、実施例３
と同一の１％ジブカイン25g、および実施例１と同一の
ホワイト・ペトロラタム2.5gとを研究室用混合容器内で
室温において混合した。得られた混合物は0.5％ニトロ
グリセリン−１％ヒドロコルチゾン−0.5％ジブカイン
軟膏の50gであった。Example 4 The same ointment of 2.5 g of 2% nitroglycerin as in Example 1 was added to 20 g of 2.5% hydrocortisone as in Example 2, Example 3
Was mixed with 25 g of the same 1% dibucaine and 2.5 g of the same white petrolatum in Example 1 at room temperature in a laboratory mixing vessel. The resulting mixture was 50 g of 0.5% nitroglycerin-1% hydrocortisone-0.5% dibucaine ointment.
実施例 ５ ある29才の女性患者は、肛門の痛みと通じに伴う出血
が７日間という病歴を有した。身体検査の結果、後正中
線肛門裂傷であった。その患者の治療前の痛みは7/10と
診断された。その患者に実施例１で調合した軟膏約500m
gを毎日３回通じの後塗布した。患者の痛みは最初の塗
布後にとれた。３週間の治療後、その裂傷は完全に治癒
した。Example 5 A 29-year-old female patient had a history of anal pain and bleeding associated with anatomy for 7 days. Physical examination revealed posterior midline anal fissure. The patient's pretreatment pain was diagnosed as 7/10. About 500m of the ointment prepared in Example 1 for the patient
g was applied three times daily after application. The patient's pain was relieved after the first application. After three weeks of treatment, the tear was completely healed.
実施例 ６ ある40才の女性患者は３ケ月間の肛門痛と通じ後の出
血という病歴を有した。身体検査結果は、表面の後正中
線肛門裂傷であった。患者の治療前の痛みは7/10と評価
された。その患者に実施例１で調合した軟膏約500mgを
毎日に３回通じの後塗布した。１週間の治療後、患者の
痛みは持続したが、痛みは2/10と評価された。３週間の
治療後、その裂傷は治癒し、痛みもなくなった。Example 6 A 40-year-old female patient had a history of anal pain and bleeding after 3 months of anal pain. The physical examination was a posterior midline anal fissure at the surface. The patient's pretreatment pain was rated at 7/10. About 500 mg of the ointment prepared in Example 1 was applied to the patient three times daily and then applied. After one week of treatment, the patient's pain persisted, but the pain was rated 2/10. After three weeks of treatment, the laceration healed and pain was gone.
実施例 ７ ある36才の男性は24時間の肛門と通じ後の出血という
病歴を有した。検査は後正中線肛門潰瘍と診断された。
治療前の痛みは9/10であった。その患者をヒドロコルチ
ゾン／プラキモシン・クリーム（商品名ANALPRAM−HC,
2.5％、Ferndale Laboratories社製品）で毎日に３回
通じ後に治療した。１週間の治療後、患者の痛みは6/10
となったが、身体の状態は本質的に変らなかった。その
患者に次に実施例２で調剤した軟膏約500mgで毎日３回
通じ後に治療した。患者は塗布毎に痛みが直ちに軽減し
たと報告した。該治療の１週間後、潰瘍は小さくなった
が、未だ完全に治癒しなかった。Example 7 A 36-year-old man had a history of bleeding after 24 hours of anus communication. Examination revealed a midline anal ulcer.
The pain before treatment was 9/10. The patient was treated with hydrocortisone / plachymosin cream (brand name ANALPRAM-HC,
(2.5%, Ferndale Laboratories product) three times daily. After one week of treatment, patient's pain is 6/10
However, his condition was essentially unchanged. The patient was then treated with about 500 mg of the ointment prepared in Example 2 three times daily after gavage. Patient reported immediate relief of pain with each application. One week after the treatment, the ulcers became smaller but still did not heal completely.
実施例 ８ ある23才の女性は１ケ月間の肛門痛と通じ後の出血と
いう病歴を有した。検査結果は、表面後正中線肛門裂傷
であった。彼女は前にヒドロコルチゾン治療コースに失
敗している。治療前の痛みは9/10であった。その患者を
実施例１で調剤した約500mgの軟膏で通じ後毎日３回治
療した。１週間の治療後、裂傷はなお存在したが、痛み
は8/10であった。次にその患者を実施例２で調剤した軟
膏約500mgで通じ後毎日３回治療した。実施例２の軟膏
で１週間治療後、患者は痛みも出血もなくなった。検査
結果、裂傷は治癒していた。Example 8 A 23 year old woman had a history of anal pain and bleeding after one month of anal pain. The test result was a posterior midline anal fissure. She has previously failed a hydrocortisone treatment course. The pain before treatment was 9/10. The patient was treated with about 500 mg of the ointment prepared in Example 1 three times daily after passing through. After one week of treatment, the laceration was still present, but the pain was 8/10. Next, the patient was treated with the ointment prepared in Example 2 about three times a day after passing through with about 500 mg. After one week of treatment with the ointment of Example 2, the patient had no pain or bleeding. Examination revealed that the laceration had healed.
実施例 ９ ある27才の女性は３日間の肛門痛と通じ後の出血とい
う病歴を有した。身体検査結果は表面の後正中線肛門裂
傷であった。治療前の痛みは4/10と評価された。その患
者を実施例２で調剤した軟膏約500mgで毎日３回通じ後
に治療した。１週間の治療後、患者の痛みは消減し、2/
10と評価された。さらに15日間の治療後、患者の痛みは
なくなり裂傷は治癒した。Example 9 A 27-year-old woman had a history of anal pain for 3 days and bleeding after she passed. Physical examination revealed a superficial posterior midline anal fissure. Pain before treatment was rated 4/10. The patient was treated with about 500 mg of the ointment prepared in Example 2 three times daily after passing. After one week of treatment, the patient's pain disappeared and
Rated 10 After another 15 days of treatment, the patient had no pain and the laceration had healed.
実施例 10 ある27才の男性は５日間の肛門痛の病歴を示した。身
体検査の結果、肛門の左前外側1/4円に1cmの血栓のでき
た外痔であった。その患者を実施例３の軟膏約500mgで
毎日３回通じ後に治療した。彼に３日後に肛門痛の著し
い減少とずきずきを報告した。Example 10 A 27-year-old man had a 5-day history of anal pain. Physical examination revealed an external hemorrhoid with a 1cm thrombus in the left anterior quarter of the anus. The patient was treated with approximately 500 mg of the ointment of Example 3 three times daily. He reported a significant decrease in anal pain and dripping three days later.
実施例 11 ある57才の男性が２年前に下部脊髄手術の後に生じた
挙筋痙縮治療について述べた。その患者を実施例１の軟
膏約500mgで肛門内を毎日３回通じ後に治療した。彼は
１日以内に肛門直腸痙縮の改善を報告した。次に治療を
実施例３の調剤に切替えて、約500mgで肛門内を毎日３
回通じ後に治療した。痛みの軽減は余り大きくなかった
ので、実施例１の調剤での治療を再開した。Example 11 A 57-year-old man described treatment for levator spasm two years ago after a lower spinal cord operation. The patient was treated with about 500 mg of the ointment of Example 1 through the anus three times daily. He reported improvement in anorectal spasticity within one day. Next, the treatment was switched to the preparation of Example 3 and the intra-anal was dosed at about 500 mg every day.
The patient was treated after the round. Since the pain relief was not so great, treatment with the preparation of Example 1 was resumed.
実施例12−グループ研究 方 法 TEHグループ:5人の患者（女性３名、男性２名）を募
って急性血栓外痔（TEH）の局所ニトログリセリン治療
の実験に酸化させた。彼等の年齢は23〜51才であった。
彼等の症状の持続期間は２〜４日であった。これらの患
者全ての肛門および直腸の検査は、肛門の1/4区（３人
の患者）および肛門の2/4区（２人の患者）にTEHを示し
た。これらの患者はいずれも内痔血栓、裂傷、腫瘍また
はフィステルの形跡を示さなかった。これらの患者の全
てに１種以上の局所調剤（Parke−Davis社の商品名ANUS
OLまたはANUSOL−HC;Whitehall Laboratoriesの商品名
PREPARATION H:Reed ＆ Carnrick社の商品名PROCTOC
REAM−HC）を使用したが症状の軽減は見られなかった。Example 12-Group Study Method TEH group: Five patients (3 women, 2 men) were recruited and oxidized to an experiment of topical nitroglycerin treatment of acute extrathrombotic hemorrhoid (TEH). Their age was 23-51.
The duration of their symptoms was 2-4 days. Examination of the anus and rectum in all of these patients showed TEH in the quarter of the anus (3 patients) and in the quarter of the anus (2 patients). None of these patients showed any signs of internal hemorrhoidal thrombus, laceration, tumor or fistula. All of these patients have one or more topical preparations (Parke-Davis trade name ANUS
OL or ANUSOL-HC; trade name of Whitehall Laboratories
PREPARATION H: Trade name of Reed & Carnrick PROCTOC
REAM-HC) was used, but no reduction in symptoms was observed.
裂傷グループ:15人の患者（女性10人と男性５人）を
募集して肛門裂傷または潰瘍の局所ニトログリセリン治
療の実験に酸化させた。彼等の年令は26〜61才であっ
た。彼等の症状の持続期間は２日〜２年に及んだ。３人
の患者は後正中線肛門潰瘍;11人の患者は急性の後正中
線裂傷し;1人の患者は急性の前正中線肛門裂傷であっ
た。２人の患者はクローン回腸炎の病歴を有した。これ
らの患者はいずれも最近の肛門手術の病歴をもたなかっ
た。Tear group: 15 patients (10 women and 5 men) were recruited and oxidized for topical nitroglycerin treatment of anal tears or ulcers. Their age was between 26 and 61. The duration of their symptoms ranged from two days to two years. Three patients had posterior midline anal ulcers; 11 patients had acute posterior midline lacerations; one patient had acute anterior midline anal lacerations. Two patients had a history of Crohn's ileitis. None of these patients had a history of recent anal surgery.
それぞれの参加者から告知承認を得た後で治療のプロ
グラムを開始した。治療は車前子（毎日12g）と必要な
坐浴を含んだ。実施例１の0.5％ニトログリセリン軟膏
約500〜1000mgを指で外肛門部に遠位肛門管に毎日４回
以上通じ後に塗布した。その治療開始後、全ての患者と
面接して１週間検査した。裂傷グループの患者は治療開
始後３週間再検査し、その後裂傷が治癒するまでまたは
８週間の治療が終る１週間または２週間毎に再検査し
た。The treatment program was started after each participant received notice and approval. Treatment included a forehead (12 g daily) and a required sitz bath. About 500 to 1000 mg of the 0.5% nitroglycerin ointment of Example 1 was applied to the external anus with a finger at least four times daily through the distal anal canal and then applied. After the start of the treatment, all patients were interviewed for one week. Patients in the laceration group were re-examined for 3 weeks after the start of treatment, and then re-examined until the healing of the laceration or every one or two weeks after the end of the 8 week treatment.
結 果 TEHグループ：全ての患者がニトログリセリンの塗布
後２〜３分以内に肛門痛の完全またはほゞ完全除去を報
告した。ニトログリセリンは特に排便後に典型的に生じ
る痛みの除去に有効である。ニトログリセリンの軟膏の
各塗布は全ての患者に４〜６時間で肛門の痛を除去し
た。全ての患者が少しの坐浴の必要性を報告した。ニト
ログリセリン軟膏を平均して３日間（２〜６日間）使用
した。通常の時間経過に従って血栓の消散が見られた。
副作用は２人の患者（グループ母集団の40％）−時間頭
痛に限定された。RESULTS: TEH group: All patients reported complete or near complete removal of anal pain within a few minutes after nitroglycerin application. Nitroglycerin is particularly effective in relieving pain that typically occurs after defecation. Each application of the nitroglycerin ointment relieved anal pain in 4-6 hours for all patients. All patients reported the need for a small bath. Nitroglycerin ointment was used on average for 3 days (2-6 days). Dissolution of the thrombus was observed over a normal time course.
Side effects were limited to two patients (40% of the group population) -time headache.
裂傷グループ：全ての患者がニトログリセリン軟膏の
塗布の３〜４分以内に肛門痛の劇的軽減を報告し、痛み
軽減の効果は２〜６時間持続した。大部分の患者が、排
便後の痛みの軽減に特にニトログリセリン軟膏が有効で
あると報告した。14人の患者は起きている間４〜６時間
毎に軟膏を塗布した。１人の患者は満足の痛みを押さえ
るのに２〜３時間毎の塗布を要した。表面の肛門裂傷の
12人の中10人（この組の80％）は２週間以内に治癒し
た。そしてこの組はクローン病の２人の患者を含んだ。
２週間で完全治癒後に治療を中断した２人の患者は裂傷
が再発した。さらに２週間の治療に応じた２人は再発の
症状を示さなかった。肛門裂傷をもった残りの２人の患
者は４週間の連続治療後に治癒した。後部肛門潰瘍の１
人の患者は改善されたが、２週間の治療後に完全治癒し
なかった。彼女は括約筋切開を求めた、その結果さらに
１ケ月以内に完治した。後部肛門潰瘍の２人の患者は改
善されたが、２ケ月の治療後にも完全治癒しなかった、
両方の場合に括約切開を拒否した。副作用は５人の患者
（グループ母集団の33％）に一時的な軽い頭痛に限定さ
れた。Tear group: All patients reported dramatic relief of anal pain within 3-4 minutes of application of the nitroglycerin ointment, and the pain relief effect lasted 2-6 hours. Most patients reported that nitroglycerin ointment was particularly effective in reducing post-fecal pain. Fourteen patients applied the ointment every 4-6 hours while awake. One patient required application every 2-3 hours to reduce the pain of satisfaction. Superficial anal fissure
Ten of the twelve (80% of this group) healed within two weeks. And this set included two patients with Crohn's disease.
Two patients who discontinued treatment after complete healing in two weeks had recurrence of the laceration. Two patients who responded for another two weeks of treatment showed no symptoms of relapse. The remaining two patients with anal fissures healed after 4 weeks of continuous treatment. Posterior anal ulcer 1
One patient improved but did not heal completely after 2 weeks of treatment. She sought an incision in the sphincter, which resulted in a complete cure within a month. Two patients with posterior anal ulcers improved, but did not heal completely after two months of treatment,
Sphinctomy was rejected in both cases. Side effects were limited to temporary mild headaches in 5 patients (33% of group population).
この研究で20人の患者が局部塗布のニトログリセリン
軟膏の初投与後に痛みの劇的軽減を経験した。そして治
癒が顕著であった。肛門および直腸部分に局所的に塗布
したニトログリセリン軟膏は、この研究において大部分
の患者によって許容された。２人の患者の中の７人（グ
ループ母集団の35％）が、ニトログリセリン軟膏の局所
塗布後に頭痛を経験した。その頭痛は一般に自己限定性
であって約15分後に軽減された。Twenty patients in this study experienced a dramatic reduction in pain after the first administration of a topical nitroglycerin ointment. And healing was remarkable. Nitroglycerin ointment applied topically to the anal and rectal areas was tolerated by most patients in this study. Seven of the two patients (35% of the group population) experienced a headache after topical application of nitroglycerin ointment. The headache was generally self-limiting and relieved after about 15 minutes.
実施例 13 ホワイト・ベテロラタム、ラノリンおよび蒸留水中の
濃度が２％のニトログリセリン（実施例１と同じもの）
8.75gとホワイト・ベトロラタム41.25g（実施例１と同
じもの）を研究室用混合容器で室温において混合するこ
とによって軟膏を調製する。得られた混合物は0.35％ニ
トログリセリン軟膏50gである。Example 13 White Veterolatam, Lanolin and 2% Nitroglycerin in Distilled Water (Same as Example 1)
An ointment is prepared by mixing 8.75 g and 41.25 g of white petrolatum (as in Example 1) in a laboratory mixing vessel at room temperature. The resulting mixture is 50 g of 0.35% nitroglycerin ointment.
その軟膏は、冒された部分またはその近傍に局所的に
塗布したとき肛門疾患の治療に有効である。それによる
痛みの軽減および治癒は顕著であり、頭痛のような副作
用は少ないまたは弱い。その軟膏はヒトに使用できる。The ointment is effective in treating anal disease when applied topically to or near the affected area. The resulting pain relief and healing is remarkable and side effects such as headaches are few or weak. The ointment can be used for humans.
結 論 以上のことから、本発明は前記発明の目的を達成する
のに適していることがわかる。Conclusion From the above, it can be seen that the present invention is suitable for achieving the object of the invention.
発明の範囲を逸脱することなく発明の多くの実施態様
が可能であるから、ここに記載した全ての事柄は説明の
ためであって限定を意味するものではない。All matters set forth herein are illustrative and not intended to be limiting, as many embodiments of the invention are possible without departing from the scope of the invention.
───────────────────────────────────────────────────── フロントページの続き 前置審査 (56)参考文献 Ｇｕｔ 1993，34 Ｓ25（Ａｐｒｉｌ 1993) Ｇａｓｔｒｏｅｎｔｅｒｏｌｏｇｙ 104（４）Ａ544（Ａｐｒｉｌ 1993) Ｂｒ．Ｊ．Ｓｕｒｇ．Ｖｏｌ．73 ｐ．443−445（1986) 日本大衆薬工業協会編「大衆薬事典’ 94〜’95（一般医薬品集＜添付書要約＞ 第４版）」薬業時報社ｐ．253，257, 262（平６−４−１) Ｐｈａｒｍａｃｏｌｏｇｉｃａｌ Ｒ ｅｖｉｅｗｓ Ｖｏｌ．43，Ｎｏ．３ ｐ．351−353（1991) (58)調査した分野(Int.Cl.7，ＤＢ名) A61K 31/21 ＣＡ（ＳＴＮ)──────────────────────────────────────────────────続 き Continuation of the front page Preliminary examination (56) References Gut 1993, 34 S25 (April 1993) Gastroenterology 104 (4) A544 (April 1993) Br. J. Surg. Vol. 73 p. 443-445 (1986) Japan Pharmaceutical Manufacturers Association, “Popular Pharmaceutical Encyclopedia '94 -'95 (General Pharmaceutical Collection <Summary of Attachment> 4th Edition)” 253, 257, 262 (Hei 6-4-1) Pharmacological Reviews Vol. 43, No. 3 p. 351-353 (1991) (58) Fields investigated (Int. Cl. 7 , DB name) A61K 31/21 CA (STN)
Claims (14)
セリンを肛門外部および遠位肛門管に塗布することによ
って、肛門疾患を処置しおよび肛門疾患に伴う疼痛を軽
減するための薬学的組成物。1. A pharmaceutical composition comprising nitroglycerin for treating anal disease and reducing pain associated with anal disease by applying the nitroglycerin to the external and distal anal canal.
セリンを肛門管に塗布することによって、肛門疾患を処
置しおよび肛門疾患に伴う疼痛を軽減するのための薬学
的組成物。2. A pharmaceutical composition containing nitroglycerin for treating anal disease and reducing pain associated with anal disease by applying the nitroglycerin to the anal canal.
に記載の薬学的組成物。3. The method according to claim 1, which is an ointment or a suppository.
A pharmaceutical composition according to claim 1.
の量で存在する、請求項１〜３のいずれか１項に記載の
薬学的組成物。4. The method according to claim 1, wherein the nitroglycerin is contained in an amount of about 0.01 to 10% by weight.
The pharmaceutical composition according to any one of claims 1 to 3, which is present in an amount of
の量で存在する、請求項１〜４のいずれか１項に記載の
薬学的組成物。5. The method according to claim 1, wherein the nitroglycerin is contained in an amount of about 0.01 to 5% by weight.
The pharmaceutical composition according to any one of claims 1 to 4, which is present in an amount of
１〜５のいずれか１項に記載の薬学的組成物。6. The pharmaceutical composition according to claim 1, further comprising a corticosteroid.
いずれか１項に記載の薬学的組成物。7. The pharmaceutical composition according to claim 1, further comprising a local anesthetic.
り、単位投薬量当たり、約2.5mg〜5mgの範囲内の量で前
記ニトログリセリンを含む、請求項１〜７のいずれか１
項に記載の薬学的組成物。8. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition is in unit dosage form and comprises said nitroglycerin in an amount in the range of about 2.5 mg to 5 mg per unit dose.
The pharmaceutical composition according to Item.
疾、および挙筋痙縮からなる群から選択される１つ以上
の疾患を含む、請求項１〜８のいずれか１項に記載の薬
学的組成物。9. The method according to claim 1, wherein said anal disease includes one or more diseases selected from the group consisting of anal fissures, anal ulcers, hemorrhoids, and levator spasm. Pharmaceutical composition.
セリンを肛門外部および遠位肛門管に塗布することによ
って、肛門疾患を処置しおよび肛門疾患に伴う疼痛の軽
減するための薬学的組成物を調製する方法であって、こ
こで、該方法は、該薬学的組成物中に該ニトログリセリ
ンを0.01〜10重量％の量で含有させる工程を包含する、
方法。10. A pharmaceutical composition for treating anal disease and reducing pain associated with anal disease, comprising nitroglycerin, and applying the nitroglycerin to the external and distal anal canal. A method, wherein the method comprises the step of including the nitroglycerin in the pharmaceutical composition in an amount of 0.01 to 10% by weight.
Method.
セリンを肛門管に塗布することによって、肛門疾患を処
置しおよび肛門疾患に伴う疼痛の軽減するための薬学的
組成物を調製する方法であって、ここで、該方法は、該
薬学的組成物中に該ニトログリセリンを0.01〜10重量％
の量で含有させる工程を包含する、方法。11. A method for preparing a pharmaceutical composition for treating anal disease and reducing pain associated with anal disease by applying nitroglycerin to the anal canal, comprising applying the nitroglycerin to the anal canal. Wherein the method comprises adding 0.01 to 10% by weight of the nitroglycerin in the pharmaceutical composition.
The method of containing in the amount of.
態である、請求項10または11に記載の方法。12. The method according to claim 10, wherein the pharmaceutical composition is in the form of an ointment or suppository.
り、単位投薬量あたり2.5〜5.0mgのニトログリセリンを
含む、請求項10〜12のいずれか１項に記載の方法。13. The method according to any one of claims 10 to 12, wherein the pharmaceutical composition is in unit dosage form and contains 2.5 to 5.0 mg nitroglycerin per unit dosage.
少なくとも１つを薬学的有効量で前記薬学的組成物中に
混合する工程をさらに包含する、請求項10〜13のいずれ
か１項に記載の方法。14. The method of claim 10, further comprising the step of mixing at least one of a corticosteroid and a local anesthetic in said pharmaceutical composition in a pharmaceutically effective amount. Method.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/250,555 US5504117A (en) | 1994-05-27 | 1994-05-27 | Pharmacologic preparation for the treatment of anal disorders |
| US37108895A | 1995-01-10 | 1995-01-10 | |
| US08/371,088 | 1995-01-10 | ||
| US250,555 | 1995-01-10 | ||
| US08/250,555 | 1995-01-10 | ||
| US371,088 | 1995-01-10 | ||
| PCT/US1995/004364 WO1995032715A1 (en) | 1994-05-27 | 1995-04-10 | Nitric oxide donor composition and method for treatment of anal disorders |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000171337A Division JP3866906B2 (en) | 1994-05-27 | 2000-06-07 | NO donor and method for treating anal disease |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH09504037A JPH09504037A (en) | 1997-04-22 |
| JP3211892B2 true JP3211892B2 (en) | 2001-09-25 |
Family
ID=26940977
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP50083596A Expired - Lifetime JP3211892B2 (en) | 1994-05-27 | 1995-04-10 | Nitric oxide donor and method for treating anal disease |
| JP2000171337A Expired - Fee Related JP3866906B2 (en) | 1994-05-27 | 2000-06-07 | NO donor and method for treating anal disease |
| JP2002243611A Withdrawn JP2003073302A (en) | 1994-05-27 | 2002-08-23 | No-donor for treating anal disease and method for the same |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000171337A Expired - Fee Related JP3866906B2 (en) | 1994-05-27 | 2000-06-07 | NO donor and method for treating anal disease |
| JP2002243611A Withdrawn JP2003073302A (en) | 1994-05-27 | 2002-08-23 | No-donor for treating anal disease and method for the same |
Country Status (16)
| Country | Link |
|---|---|
| US (4) | US5693676A (en) |
| EP (2) | EP0719145B1 (en) |
| JP (3) | JP3211892B2 (en) |
| KR (1) | KR100386525B1 (en) |
| CN (1) | CN1107499C (en) |
| AT (2) | ATE196082T1 (en) |
| AU (1) | AU2282395A (en) |
| CA (1) | CA2168247C (en) |
| DE (3) | DE69518729T2 (en) |
| DK (2) | DK1051972T3 (en) |
| ES (2) | ES2292402T3 (en) |
| GR (2) | GR960300077T1 (en) |
| HK (1) | HK1032545A1 (en) |
| IL (1) | IL113448A (en) |
| PT (2) | PT719145E (en) |
| WO (1) | WO1995032715A1 (en) |
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- 1995-04-10 EP EP95916264A patent/EP0719145B1/en not_active Revoked
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